ABSTRACT/PROJECT SUMMARY This application seeks support for a phased project. In the initial (R61) 2-year phase we will establish that Cognitive Remediation Therapy (CRT) can increase set-shifting in parents of and/or adolescents with Anorexia Nervosa (AN). Our second aim is to determine the appropriate dose needed to achieve positive change in set- shifting. Attaining our milestone would trigger support for three additional years (R33) to confirm target engagement and appropriate dose. We will also evaluate whether or not adding CRT to Family Based Treatment (FBT) will improve outcome compared to FBT alone. Set-shifting (a type of executive functioning often referred to as cognitive flexibility) inefficiencies are hypothesized to be an endophenotype of AN and are, therefore, heritable. Cognitive flexibility can be impacted negatively by situational factors such as malnutrition, stress, and anxiety. It is likely that both adolescents (who are malnourished) and parents (who are under stress) experience significant state-based reduction in their cognitive flexibility during AN and its treatment. While cognitive flexibility can be increased through CRT, there is a significant gap in our knowledge about how to apply CRT to the treatment of adolescent AN, specifically concerning the most appropriate target for CRT: parents or adolescents? The majority of research on CRT with adolescents with AN are pilot and feasibility studies and target set-shifting in adolescents, not parents. We hypothesize that targeting parents may be more impactful for adolescent outcome. First, we must determine if we can increase set-shifting via CRT. In the initial R61 phase we propose to recruit and randomly assign 54 families who have a child with AN to FBT, FBT with parent-focused CRT, or FBT with adolescent-focused CRT. Target engagement will be assessed via neuro- psychological assessment and self-report of cognitive and behavioral flexibility. If we meet our proposed milestones in the R61 phase, we will proceed to the R33 phase. It is possible that one (N = 72 families) or both (N = 93 families) CRT conditions will be examined in the R33 phase. We will confirm our findings from the R61 phase (target engagement and dose of CRT). We will also examine adolescent outcome in FBT alone versus FBT+(parent or adolescent) CRT. Outcome includes rate of weight gain, cognitive symptoms of AN, and variety in macronutrient intake by the adolescent. We will gather preliminary data on putative moderators and/or mediators across both phases in order to inform results. This phased R61/R33 application is innovative in that it is the first to adapt CRT to parents only. Evidence supporting FBT+CRT to increase set-shifting in parents/adolescents will inform future efforts to leverage our understanding of (heritable) neurobiology of AN in adolescents to improve outcome. Further, if CRT for parents significantly improves set-shifting, we can focus our efforts on how best to augment current treatments, support parents, and increase positive outcomes for the adolescent and reduce relapse. Even negative results would inform our understanding of set-shifting inefficiencies as an endophenotype in AN, its measurement, and usefulness as a target in treatment.